This proposal is for an Independent Scientist Award (K02). This award will provide the candidate with release time to expend her research skills and enhance her ability for scientific investigations and mentoring. The candidate has demonstrated that chronic morphine use or abuse is associated with an increased incidence of many diseases, and animal studies have demonstrated that morphine can alter a number of immune parameters. Although these effects of morphine are very well established, it still remains unresolved the receptor type involved in morphine mediated effects on immune parameters. In addition it is still controversial if it is the central mu-opioid receptors or receptors present on target cells that mediates morphine's immunosuppressive effects. The objective of this proposal is to determine the contribution of these receptors in modulating the immune system and to gain insight into the intracellular mechanisms by which morphine mediates its effects. The research plan is to investigate the role of Mu-opioid receptors in morphine mediated immunosuppression by using wild type and MORKO mice. These studies will include the role of Mu receptors in the brain and its role in hypothalamic-pituitary-adrenal axis activation. Subsequently, the proposal will investigate the relative role of peripheral Mu opioid receptors in morphine mediated immunosuppression. The mechanisms by which Mu-opioid receptors modulate cytokine gene expression will also be studied. Finally, mRNA will be isolated from the immune cells of MORKO mice following chronic morphine treatment and gene families that are altered will be investigated using gene array technology. In addition collaboration with several investigators experienced with a) T-cell biology b) Opioid induced G-protein coupling c) viral infections and d) Gene array technology will contribute enormously to the overall enhancement of the quality and depth of the PI research program.